Abstract Chronic liver diseases are the 12th leading cause of mortality and among the most common causes of morbidity in the U.S. with 5.5 million people suffering from the diseases. Currently, liver transplantation is the only effective treatment for end-stage liver diseases; however, the shortage of donor livers makes this therapy extremely limited, thus necessitating alternative therapies. Promoting innate liver regeneration in chronic liver diseases is an attractive alternative. Upon liver injury, hepatocytes proliferate to yield more hepatocytes to restore lost liver mass and maintain liver function. However, when hepatocyte proliferation is compromised, a phenomenon observed in advanced liver diseases, liver progenitor cells (LPCs) are activated and these LPCs expand and eventually differentiate into hepatocytes. Thus, it is crucial to understand the molecular mechanisms of LPC- driven liver regeneration, which will provide significant insights into promoting this process as a pro-regenerative therapy for advanced liver diseases. Particularly, given the prevalence of LPCs in chronically diseased livers, promoting LPC differentiation into functional hepatocytes will be a promising pro-regenerative therapy. We have established a zebrafish liver injury model in which hepatocyte-specific overexpression of oncogenes induces oncogene-induced hepatocyte damage, such as senescence and apoptosis, followed by inflammation, LPC activation, fibrosis and eventually LPC-mediated liver repair. Using this chronic liver injury model as a screening tool for identifying small molecules that can promote LPC differentiation into hepatocytes, we discovered that treatment with EGFR inhibitors promoted LPC differentiation into hepatocytes, thereby enhancing liver repair/recovery. In addition to the zebrafish model, we have established a mouse liver injury model for LPC- driven liver regeneration. This mouse model allows us to determine if EGFR inhibition can promote LPC differentiation into hepatocytes in mammals as in fish. Here, we propose to determine the effect of EGFR inhibition on LPC differentiation and the role of EGFR signaling in LPC-driven liver regeneration by pursuing three specific aims. Aim 1: Using two zebrafish models of hepatocyte-specific oncogene overexpression, we will elucidate the process of LPC-driven liver regeneration in oncogene-induced liver damage settings. Aim 2: Using the zebrafish and mouse liver injury models for LPC-driven liver regeneration, we will determine the effects of EGFR inhibition on LPC differentiation into hepatocytes and subsequent liver recovery. Aim 3: We will determine the molecular mechanisms controlling LPC differentiation by investigating the role of EGFR and Sox9 in this differentiation process. Successful accomplishment of the proposed work will not only significantly advance the mechanistic understanding of liver regeneration in the diseased liver, but also lay the groundwork for use of EGFR inhibitors as a promising pro-regenerative agent to augment LPC-driven liver regeneration in patients with advanced liver diseases.